Theravance and Janssen's Oral Gut-Restricted JAK Inhibitor Izencitinib Fails to Meet Primary Endpoint in Phase 2 Ulcerative Colitis Trial

Compiled by | Fan Dongdong

Izencitinib, a drug for ulcerative colitis, is the lead program in the collaboration between Theravance Biopharma and Johnson & Johnson subsidiary Xian Janssen. Recently, the drug's failure to meet the primary endpoint in a Phase 2 dose-ranging study for ulcerative colitis has cast doubt on the prospects of this JAK inhibitor for indications including ulcerative colitis.

In 2018, Xian Janssen initiated a partnership with Theravance with an upfront payment of $100 million, committing to an additional $900 million in potential milestone payments. The most advanced candidate in this collaboration is izencitinib, an oral drug designed to inhibit Janus kinase (JAK) enzymes involved in inflammatory processes. Notably, in 2019, Pfizer also entered into a JAK inhibitor collaboration with Theravance to develop skin-targeted topical anti-inflammatory therapies. Targeting validated pro-inflammatory pathways, these compounds are specifically designed to exhibit skin-selective activity with minimized systemic exposure.

Previously, other JAK inhibitors on the market had already entered the autoinflammatory disease space (such as rheumatoid arthritis), whereas Theravance has focused the development of izencitinib on gastrointestinal diseases, with inflammatory bowel disease—specifically ulcerative colitis—as its primary potential indication. The drug is designed to localize its therapeutic action within the patient's intestinal tract. In contrast, currently marketed JAK inhibitors exert systemic effects via the bloodstream, thereby carrying a higher risk of adverse events (including cardiovascular complications and infections).

This Phase 2 trial enrolled a total of 239 patients, who were randomized to receive one of three doses of izencitinib or placebo, administered once daily for 8 weeks. The primary endpoint of the study was the change in ulcerative colitis severity as measured by clinical assessment scales in patients treated with izencitinib compared with placebo. However, according to the trial results reported by Theravance, patients receiving any dose of izencitinib did not demonstrate improvement in ulcerative colitis severity. Clinical response exhibited a slight dose-dependent increase, which the company attributed to a reduction in rectal bleeding.

Although efficacy outcomes across all dose groups were disappointing, Theravance noted that patients receiving the three doses of izencitinib demonstrated favorable tolerability, with adverse event rates comparable between the treatment and placebo groups. During the trial, no patients experienced intestinal perforation, opportunistic infections, or major cardiovascular events. Commenting on the overall failure of this Phase 2 dose-ranging trial, Theravance CEO Rick E. Winningham stated that the company will continue to analyze the trial data to better understand the implications for the future development of izencitinib. The company is still awaiting study results at the 16-week and 44-week treatment timepoints. Theravance plans to present the available trial results at upcoming scientific conferences.

Worldwide, over 5 million individuals are affected by inflammatory bowel disease (IBD), which primarily encompasses ulcerative colitis and Crohn’s disease. IBD is a chronic, relapsing-remitting condition characterized by intestinal inflammation and tissue damage, accompanied by associated symptoms such as abdominal pain, frequent and persistent diarrhea, weight loss, rectal bleeding, and fatigue. Currently, there is no cure for IBD. Treatment regimens are typically selected based on the severity of disease activity and the patient's response to therapy. The primary goal of treatment is to reduce the underlying inflammation, thereby achieving short-term or long-term remission and minimizing the risk of complications.

Given that the ulcerative colitis data fell short of expectations, Theravance stated that it will minimize future R&D expenditures on izencitinib. However, Crohn's disease remains among the indications for izencitinib still under development. Winningham noted that a Phase 2 clinical trial of the drug in this indication is currently underway, and Theravance had previously anticipated that preliminary trial data would be released later this year or in early 2022.

References:

1.Theravance’s Janssen Biotech-partnered ulcerative colitis drug flops in Phase 2

2.Theravance Drug Candidate for Ulcerative Colitis Fails To Meet Primary Endpoint